Organic hydroxyl substituents are advantageously protected during chemical reactions as alkoxy methyl ethers. One example of such protection is seen in the preparation of Ciramadol in U.S. Pat. No. 3,928,626. These ethers are conventionally produced in small quantities by reaction of a molar excess of chloromethyl ether (CH.sub.3 OCH.sub.2 Cl) with a phenolic hydroxyl group at reflux temperature in dry acetone and in the presence of a large excess of anhydrous potassium carbonate. Edwards et al., J. Chem. Soc., 1967, pp. 411-413 (Experimental). The preparative procedure is not desirable in commercial or pilot plant scale production of protected phenols because chloromethyl ether is extremely carcinogenic.
To avoid use of chloromethyl ether in the production of protected hydroxyl groups, various techniques have been developed, each of which presents its own processing disadvantages. For example, Fuji et al., Synthesis (1975) 276, report upon a method for introduction of the methoxymethyl protecting group involving the reaction of methylal(dimethoxymethane) with an alcohol in the presence of phosphorus pentoxide. This method is undesireable because on a production scale above that employed in the laboratory, the handling of insoluble phosphorus compounds (two moles of phosphorus pentoxide is employed for each mole of the hydroxy compound) becomes a major problem.
Yardley et al., Synthesis (1976) 244, modified the acid catalyst in the acetal exchange reaction by using p-toluene sulfonic acid as the acid catalyst and a molecular sieve to remove methanol as a azeotrope with dichloro methane, thereby driving the reaction toward completion and a respectable yield. This procedure, in addition to the disadvantage of a molecular sieve for methanol removal, required extended reaction times of up to about forty-eight hours to obtain a satisfactory yield. Olah et al., Synthesis (1981) 471, further modified the acid catalyzed acetal exchange reaction by using a perfluorinated solid superacidic Nafion-H catalyst to avoid the tedious aqueous basic work-up conditions of the previously mentioned procedures. This procedure otherwise offers no commercial advantage.
In lieu of methylal as the reactant, ethylal (diethoxymethane) has been used to afford ethoxymethyl ether groups in protection of organic hydroxyl substituents. This procedure, requiring an effective fractionating column to separate the ethanol formed during the process and to drive the reaction toward completion, is illustrated by Schaper, Synthesis (1981) 794.